Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Biomed Pharmacother. 2010 Dec;64(10):712-7. doi: 10.1016/j.biopha.2010.09.014.
The renin-angiotensin system (RAS) plays critical roles in the pathogenesis of atherosclerosis. Clinical studies demonstrate that pharmacological blockade of RAS with Angiotensin II type 1 receptor (AT1R) blockers (ARBs) is effective in the treatment of patients with cardiovascular diseases. Recent studies reported that telmisartan, an ARB, has a partial agonistic effect on peroxisome proliferator-activated receptor-gamma (PPAR-γ). The role of PPAR-γ-mediated signaling has been implicated in regulation of not only metabolic disorders but also atherosclerosis. Here, we investigated the effects of telmisartan, which is not related to AT1R blockade, using AT1aR and apolipoprotein E (ApoE) double-deficient (ApoE-/-AT1R-/-) mice in vivo. Both genetic ablation of AT1R in ApoE-deficient (ApoE-/-) mice and administration of telmisartan (10 mg/kg/day) to ApoE-/- mice for 20 weeks reduced the development of atherosclerosis (P<0.05, respectively). Telmisartan decreased lipid deposition (P<0.01) and increased collagen contents (P<0.05) in plaques in ApoE-/- mice. Administration of telmisartan to ApoE-/-AT1aR-/- mice also inhibited the progression of atherosclerosis in aorta (P<0.05) even in mice, which have no AT1aR genetically. Moreover, in these mice, telmisartan decreased macrophage accumulation and lipid deposition, and increased collagen contents in plaques in aortic root (P<0.05, respectively), indicating stabilization of plaques. Telmisartan-treated ApoE-/-AT1aR-/- mice showed lower body weight and higher plasma high-density lipoprotein levels compared with vehicle-treated mice (P<0.05, respectively). Telmisartan lowered systolic and diastolic blood pressure in ApoE-/-AT1aR-/- mice (P<0.01). These results suggest that telmisartan has protective effects on the development of atherosclerosis and metabolic disorders beyond AT1R blockade in ApoE-deficient mice.
肾素-血管紧张素系统（RAS）在动脉粥样硬化的发病机制中起关键作用。临床研究表明，用血管紧张素 II 型 1 型受体（AT1R）阻滞剂（ARB）抑制 RAS 的药理学阻断在治疗心血管疾病患者方面是有效的。最近的研究报告称，ARB 替米沙坦对过氧化物酶体增殖物激活受体-γ（PPAR-γ）具有部分激动作用。PPAR-γ介导的信号转导作用不仅与代谢紊乱有关，而且与动脉粥样硬化有关。在这里，我们使用体内 AT1aR 和载脂蛋白 E（ApoE）双缺失（ApoE-/-AT1R-/-）小鼠研究了替米沙坦的作用，替米沙坦与 AT1R 阻断无关。在 ApoE 缺陷（ApoE-/-）小鼠中基因敲除 AT1R 以及替米沙坦（10mg/kg/天）给药 20 周均可降低动脉粥样硬化的发展（分别为 P<0.05）。替米沙坦降低了 ApoE-/-小鼠斑块中的脂质沉积（P<0.01）并增加了胶原含量（P<0.05）。替米沙坦给药也抑制了主动脉中 ApoE-/-AT1aR-/-小鼠的动脉粥样硬化进展（P<0.05），即使在没有 AT1aR 基因的小鼠中也是如此。此外，在这些小鼠中，替米沙坦降低了主动脉根部斑块中的巨噬细胞积累和脂质沉积，并增加了胶原含量（分别为 P<0.05），表明斑块的稳定性。与载体处理的小鼠相比，替米沙坦处理的 ApoE-/-AT1aR-/-小鼠的体重较低，血浆高密度脂蛋白水平较高（分别为 P<0.05）。替米沙坦降低了 ApoE-/-AT1aR-/-小鼠的收缩压和舒张压（P<0.01）。这些结果表明，替米沙坦除了在 ApoE 缺陷小鼠中阻断 AT1R 之外，对动脉粥样硬化和代谢紊乱的发展具有保护作用。
